The goal of this Program is to establish a drug design cycle aimed at developing, testing and refining novel approaches to specific inhibitors of HIV-1 protease capable of limiting or eliminating drug resistance. Our contribution to this goal will be in the development and application of new chemical, biological and computational approaches that connect the structural and molecular basis of drug interaction to the clinical response. The program consists of four integrated Projects and two supporting Core facilities: 1) Computational modeling including atomic detail co-evolution of HIV-protease drug resistance, modeling viral population dynamics under drug selection pressure, and application of automated learning approaches to inform and refine these models and related experimental work in the other Projects. 2) Design and development of nextgeneration inhibitors using rational and combinatorial synthetic techniques targeting both the protease and associated RNA structures. 3) Application of "Click Chemistry" in situ synthetic approaches for rapid development and evolution of inhibitors to drug resistant proteases; 4) Investigation of the progression and limits of HIV protease variability by exploiting tissue-culture time-course evaluation, phage display libraries and protease targeted RNA aptamer selection. 5) The Protein Expression and Analysis Core will provide mutant and synthetic proteases, functional assays, chemical probes, and inhibitor analyses for the Program. 6) The Structure and Modeling Core will provide the necessary structural data and analysis to integrate new information on protease mutants, and protease-inhibitor interactions, as well as RNA aptamer-protein and RNA-inhibitor interactions. The successful implementation and the application of the resulting knowledge to therapeutic targets, would be a major contribution to the field of drug development and will be important in the design of new, more efficacious AIDS therapeutics.